DESCRIPTION (provided by investigator): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-HL-104: Assess genetic variation in African Americans and determine its effect on disease. Genome-wide association studies (GWAS) have successfully identified genomic loci associated with hypertension and its risk factors in recent years. However, previous GWAS were conducted in populations of European ancestry rather than populations of African Ancestry. Resources are lacking for imputation of existing single nucleotide polymorphisms (SNPs) or for the assessment of copy number variations (CNVs) and their relation to disease in individuals of African ancestry. National Heart, Lung and Blood Institute (NHLBI) has recommended an increased focus on the examination of the genetic variants (SNPs and CNVs) and their associations with common disease traits in the cohorts of African Americans. African Americans are an admixed population with both European and African ancestries. The population genetics (eg. linkage disequilibrium and allele frequencies) of African Americans are appreciably different from either of their ancestries. To appropriately design and conduct the GWAS of heart disease in African Americans, the characteristics of the genome-wide markers, such as single nucleotide polymorphism (SNP) and copy number variation (CNV), and the performance of the necessary tools for statistical analyses, such as genotype imputation and CNV calling, have to be assessed and evaluated in African American samples. The Genetic Epidemiology Network of Arteriopathy (GENOA) and HyperGEN were both initiated in 1995 to study the genetics of hypertension and its target-organ complications in sibships in multiple ethnic groups. Both cohorts have measured 906,600 SNPs and 946,000 CNV probes using Affymetrix 6.0 array on their African American subjects. In this application, we propose to estimate the characteristics of population genetics, to evaluate the performance of existing GWAS analysis tools, and to conduct a genome-wide association study of blood pressures and echocardiography traits, utilizing SNPs and CNVs identified on 1,854 African Americans from the GENOA and 1,802 African Americans from the HyperGEN, with the following specific aims: Aim 1. To characterize the distribution of copy number variations (CNVs) in African American populations, we will apply two CNV calling methods, Canary and HelixTree CNAM, using all genome-wide SNP probes and CNV probes on the Affymetrix 6.0 array. The results will be compared using two independent African American populations from the GENOA and HyperGEN studies. Aim 2: To identify genome-wide regions containing evidence of disease susceptibility loci for hypertension, obesity, left ventricular hypertrophy, and kidney function, we will perform analyses in each African American populations to identify associated CNVs and SNPs. To reduce false positives, associations will be adjusted for multiple testing and population substructure, and compared for replication. Pooled analysis will be conducted to increase power to identify associated genetic variants by combining results from GENOA and HyperGEN. Aim 3: To evaluate the performance of existing genotype imputation methods for African Americans, we will compare the performance of different imputation methods (MACH, IMPUTE and BEAGLE) in two African American populations. To improve the imputation accuracy of African American subjects, we will sequence genomic regions with poor imputation accuracy to understand the LD structure and identify the causes of inaccurate imputation. PUBLIC HEALTH RELEVANCE: The genetic variants in the human genome and their associations with cardiovascular diseases and hypertension have been inadequately studied in African American populations. Using the available genotyping data of 906,600 SNPs and 946,000 copy number variation (CNV) probes, and previously collected epidemiological data on 3,658 African Americans (1,854 GENOA and 1,804 HyperGEN), we will investigate the characteristics of population genetics (SNPs and CNVs), and conduct genome-wide association analyses of hypertension risk factors and sequelae. The characteristics of population genetics and the significant CNV effects will be replicated in two independent African American populations from GENOA and HyperGEN.